Sorafenib Tosylate in Treating Patients With Liver Cancer That Cannot Be Removed by Surgery
|Advanced Adult Hepatocellular Carcinoma Localized Non-Resectable Adult Hepatocellular Carcinoma Stage III Childhood Hepatocellular Carcinoma Stage IIIA Hepatocellular Carcinoma Stage IIIB Hepatocellular Carcinoma Stage IIIC Hepatocellular Carcinoma Stage IV Childhood Hepatocellular Carcinoma Stage IVA Hepatocellular Carcinoma Stage IVB Hepatocellular Carcinoma||Other: Laboratory Biomarker Analysis Drug: Sorafenib Tosylate|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Granzyme B Production as a Biomarker for the Immunomodulatory Activity of Sorafenib in HCC|
- Granzyme B levels [ Time Frame: Up to 35 days ]The pGrzB hazard ratio (per 10 percentage point increase) and the associated 95% confidence interval will be estimated using a Cox PH model. Whether pGrzB measurements vary by presence of grade 3+ adverse events (AEs) will be assessed using permutation independent sample t-tests. Descriptive statistics include the pGrzB mean, standard deviations and ranges within AE or patient characteristics.
- Overall survival (OS) [ Time Frame: Time between start of first treatment and death, assessed up to 6 months ]The hazard ratio and 95% confidence interval for the effect of day ~28-35 pGrzB (in 10 percentage point increments) on OS will be estimated using proportional hazards (PH) models. The pGrzB functional form will be assessed using generalized additive models. Possible confounding from sorafenib dose differences and baseline characteristics will be assessed by including other covariates (or perhaps frailty terms) in the model.
- Granzyme B level variations by presence of grade 3 or higher AE, characterized using National Cancer Institute Common Terminology Criteria for Adverse Events severity grade [ Time Frame: Up to 30 days ]These differences will be assessed using permutation independent sample t-tests. For an AE observed in 15 (50%) of the patients and two-sided statistical significance threshold = 0.05, this test has 80% power to detect a 1.0 standard difference in mean pGrzB. 95% confidence limits for the difference in mean pGrzB will also be provided. Descriptive statistics include the pGrzB mean, standard deviations and ranges within AE or patient characteristics.
- Change in granzyme B levels after sorafenib tosylate treatment [ Time Frame: Baseline to up to 35 days ]The hypotheses of immediate (HI) and sustained improvement (HS) of immune function will be tested using a fixed-sequence procedure. Each hypothesis uses a permutation paired t-test with an upper 1-sided 0.05 significance threshold. HI considers a pGrzB increase between days 0 & ~28-35. If the HI test finds no short-term pGrzB improvement, the HS test will not be done. If HI indicates a short-time pGrzB improvement, HS considers a pGrzB increase between days 0 and 24 weeks (± 1 week). If both tests indicate improvements it will be concluded improved & sustained pGrzB response follows sorafenib.
- Proportion of cluster of differentiation (CD)8+ T cells expressing granzyme B [ Time Frame: Up to 24 weeks ]
|Actual Study Start Date:||November 18, 2013|
|Estimated Study Completion Date:||August 3, 2018|
|Estimated Primary Completion Date:||August 3, 2018 (Final data collection date for primary outcome measure)|
Experimental: Treatment (sorafenib tosylate)
Patients receive sorafenib tosylate PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Sorafenib Tosylate
I. To determine whether the proportion of cytotoxic T lymphocytes that are producing granzyme B (denoted pGrzB) as measured ~28-35 days after initiation of sorafenib (sorafenib tosylate) therapy correlates with overall survival, defined as the number of months between the start of sorafenib treatment and death from any cause.
I. To determine whether higher pGrzB levels will correlate with better sorafenib tolerance, manifested by fewer dose reductions, dose interruptions and adverse events.
II. To determine whether improved immune function may also result in greater recognition of hepatitis viral antigens.
Patients receive sorafenib tosylate orally (PO) twice daily (BID). Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study, patients are followed up for 30 days or after the 6 month time point if continuing sorafenib tosylate and then periodically thereafter.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02072486
|United States, New York|
|Roswell Park Cancer Institute|
|Buffalo, New York, United States, 14263|
|Principal Investigator:||Renuka Iyer||Roswell Park Cancer Institute|